Development of VN/14-1 and Related Analogs for Breast Cancer Therapy

用于乳腺癌治疗的 VN/14-1 及相关类似物的开发

• 批准号: 8474704
• 负责人: VINCENT Collins Ofuka NJAR
• 金额: $ 47.08万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8474704
• 关键词: Acute Promyelocytic Leukemia; Advanced Development; Adverse effects; Adverse reactions; Agreement; All-Trans-Retinol; Androgen Receptor; Apoptotic; Applications Grants; Aromatase Inhibitors; Baltimore; Binding; Biological Availability; Biological Markers; Breast; Breast Cancer Cell; CYP17A1 gene; Cancer Cell Growth; Cancer Patient; Cancer cell line; Catabolism; Cell Cycle Arrest; Cells; Characteristics; Clinical; Clinical Research; Clinical Trials; Cytochrome P450; Data; Development; Differentiation Therapy; Disease; Dose; Down-Regulation; Drug Compounding; Drug Kinetics; Drug Stability; Drug resistance; Endocrine; Ensure; Enzymes; Epidemiology; Epithelial; Epithelial Cells; Estradiol; Estrogen Antagonists; Estrogen Receptors; Estrogen receptor positive; Exhibits; Fibroblasts; Foundations; Generations; Goals; Growth; Half-Life; Health; Histone Deacetylase Inhibitor; Human; Hyperplasia; Imidazole; In Vitro; Incidence; Individual; Institution; Investigational Drugs; Isomerism; Isotretinoin; Lead; Legal patent; Licensing; Literature; MCF7 cell; Malignant neoplasm of prostate; Mammary gland; Maryland; Metabolic; Metabolism; Methylnitrosourea; Microarray Analysis; Modeling; Molecular Target; Mus; NCOA3 gene; Nature; Neoplasm Metastasis; Neuroblastoma; New Agents; New Drug Approvals; Oncogenes; Oral; Outcome; PC3 cell line; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phenotype; Plasma; Postmenopause; Prevention; Probability; Prodrugs; Property; Prospective Studies; Rattus; Refractory; Reporting; Research Design; Resistance; Resources; Retinoid Receptor; Retinoids; Role; Selective Estrogen Receptor Modulators; Solid; Tamoxifen; Technology; Testing; Therapeutic; Therapeutic Index; Toxic effect; Toxicology; Tretinoin; Universities; Uterus; Vitamin A; Woman; Work; Xenograft Model; Xenograft procedure; analog; anticancer research; base; cancer therapy; capsule; design; effective therapy; enantiomer; genetic regulatory protein; hormone therapy; human study; improved; in vivo; in vivo Model; inhibitor/antagonist; malignant breast neoplasm; mortality; novel; outcome forecast; phase 1 study; pre-clinical; preclinical study; receptor; response; small molecule; success; tumor; tumor growth

DESCRIPTION (provided by applicant): Introduction: Epidemiological evidence highlights the influence of vitamin A (retinol) and its active metabolite, all-trans retinoic acid (ATRA) on the incidence of breast and prostate cancers in humans. ATRA is required for the appropriate cellular differentiation of normal human breast epithelial cells. In a 12-year prospective study of 208 postmenopausal women operated on for breast cancer, it was recently reported that low plasma retinol strongly predicts poorer prognosis in patients. Work by our group has identified novel and potent inhibitors of CYP26 enzymes responsible for intracellular catabolism of ATRA into inactive metabolites. These CYP26 inhibitors are also called retinoic acid metabolism blocking agents (RAMBAs). Our novel agents, in addition to inhibiting ATRA metabolism, also possess multiple desirable anti-breast cancer properties, and hence are called atypical RAMBAs. Our lead compound, 4-(1)-(1H-imidazol-1-yl)-(E)-retinoic acid (VN/14-1) exhibits exceptional anti-tumor efficacy in several endocrine-sensitive and insensitive (i.e., tumors that are resistant to mainstay breast cancer therapies such as tamoxifen and aromatase inhibitors) breast cancer xenograft models. VN/14-1 also inhibits the growth of tumors in the N-methyl-N-nitrosourea (MNU)-induced estrogen receptor (ER) positive rat mammary model and antagonizes the stimulatory effect of estradiol on the uterus. In contrast to its effects on several breast cancer cell lines, the compound exhibits virtually no growth inhibition (at concentrations up to 100 ?M) of normal human breast epithelial and fibroblast cells. The University of Maryland, Baltimore (UMB, the PI's former institution) has entered into a clinical research agreement with Cancer Research UK (CRUK) to conduct the first in human study of VN/14-1. Chesapeake BioDiscovery Management LLC (CBDM), Baltimore has recently licensed the entire RAMBAs technology from UMB. It may also be relevant to state here that in another project, a CYP17 inhibitor /androgen receptor modulator, VN/124-1 (now called TOK-001) invented by the PI of this application recently received FDA investigational new drug (IND) approval for phase I/II clinical trials in prostate cancer patients. Although VN/14-1 has outstanding oral bioavailability (%F >100%) in rat and anti-tumor efficacy, it has a short half-life of 0.34 and 1.41 hr, in mouse and rat, respectively. Therefore, in this application, one of our goals is to design and synthesize new analogs with improved in vivo stability and with anti-breast cancer activities as VN/14-1 or better. We envision that such agent would possess enhanced efficacy and a larger therapeutic index than VN/14- 1. In addition, we propose to investigate the therapeutic potential and mechanisms of action the new lead compounds and either of the two enantiomers of VN/14-1, i.e., (+) and (-)-VN/14-1. This strategy is based on several literature precedents which show that the enantiomers in a chiral compound/drug generally show significant differences in their pharmacokinetics (PK), pharmacodynamics (PD) and adverse reactions. Therefore, it is important to know the individual isomer effects on the potency, drug-likeness and efficacy so that we can avoid the adverse effects of the other isomer, if any. Hypothesis: Using our lead racemic VN/14-1, we have established proof-of-principle of the efficacy of this class of RAMBAs in many in vitro and in vivo models of human and murine breast cancers. The major hypothesis to be tested as described in this revised application is that development (identification) of 2nd generation atypical RAMBAs, new analogs of VN/14-1 with enhanced metabolic stability, drug-likeness and efficacy can potentially be developed as new therapy for breast cancer (inhibition of tumor growth and metastasis). Objectives: To test this hypothesis, and to maximize the probability of achieving our ultimate goal while using resources most efficiently, we will carry out four specific aims: 1) To synthesize enantiomers of lead VN/14-1 and to modify VN/14-1 to produce more potent/metabolically stable/efficacious drug-like analogs; 2) To extensively characterize and evaluate new analogs as RAMBAs and as anti-proliferative agents of human breast cancer cells; 3) To determine the mechanism of action of the lead compound and best analogs in human breast cancer cell line; and 4) To test the lead compound and best analogs for their ability to inhibit breast cancer growth, inhibit breast cancer metastasis in vivo and identify markers of efficacy. Significance: Our ultimate goal is to discover and develop new orally active drugs for breast cancer capable of inhibiting the growth of tumor cells and metastasis. Importantly, the atypical RAMBAs inhibit both endocrine- sensitive and endocrine resistant (refractory to endocrine therapies) breast cancers, and also antagonize uterine hyperplasia, characteristics that are distinct from those of selective estrogen receptor modulators (SERMs), such as tamoxifen and aromatase inhibitors (AIs). The proposed studies if successfully conducted will identify at least one or two highly optimized, orally efficacious atypical RAMBAs suitable for advanced preclinical development for breast cancer therapy. The studies would also lead to the identification of biomarkers that would be useful in clinical trials.

描述（由申请人提供）：简介：流行病学证据突出了维生素A（视黄醇）及其活性代谢物，全反式视黄酸（ATRA）对人类乳腺癌和前列腺癌的发生的影响。正常人乳腺上皮细胞的适当细胞分化需要ATRA。在一项为期12年的前瞻性研究中，对208名绝经后妇女进行了乳腺癌的运作，最近据报道，低血浆视黄醇可预测患者的预后较差。我们小组的工作确定了导致ATRA细胞内分解代谢为无活性代谢产物的新型CYP26酶的新型和有效的抑制剂。这些CYP26抑制剂也称为视黄酸代谢阻断剂（Rambas）。除了抑制ATRA代谢外，我们的新型药物还具有多种理想的抗乳腺癌特性，因此称为非典型Rambas。我们的铅化合物，4-（1） - （1H-咪唑-1-基） - （e） - 逆转酸（VN/14-1）在几种内分泌敏感和不敏感的几种内分泌敏感和不敏感的肿瘤中表现出异常的抗肿瘤功效（即，抗tamoxifen and aromatise cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer cancer and tay肿瘤（即抗肿瘤）。 VN/14-1还抑制了N-甲基N-硝基（MNU）诱导的雌激素受体（ER）阳性大鼠乳腺模型的肿瘤生长，并拮抗雌二醇对子宫的刺激作用。与其对几种乳腺癌细胞系的影响相反，该化合物几乎没有抑制正常的人乳腺上皮细胞和成纤维细胞的生长抑制（浓度高达100？m）。马里兰州大学巴尔的摩大学（PI的前机构UMB）已与英国癌症研究（CRUK）签订了临床研究协议，从事VN/14-1研究的首次研究。 Chesapeake Biodiscovery Management LLC（CBDM），巴尔的摩最近已从UMB获得了整个Rambas技术的许可。也可能与这里指出，在另一个项目中，CYP17抑制剂/雄激素受体调节剂VN/124-1（现称为TOK-001）由该应用程序的PI发明了最近获得的FDA研究新药（IND）新药（IND）批准了PROSTATE癌症患者的I/II期临床试验。尽管VN/14-1在大鼠和抗肿瘤功效中具有出色的口服生物利用度（％F> 100％），但在小鼠和大鼠中，它的半衰期分别为0.34和1.41小时。因此，在此应用中，我们的目标之一是设计和合成具有改进体内稳定性的新类似物，并以VN/14-1或更高的方式进行抗胸腺癌活动。我们设想，这种药物将具有增强的功效和更大的治疗指数。此外，我们建议研究作用的治疗潜力和机制，新的铅化合物以及VN/14-1的两个对映异构体，即，即，即，（+）和（+）和（+） - vn/14-1。该策略基于几种文献先例，这些文献表明，手性化合物/药物中的对映异构体通常在其药代动力学（PK），药效学（PD）和不良反应上显示出显着差异。因此，重要的是要了解单个异构体对效力，毒品和功效的影响，以便我们可以避免其他异构体的不利影响（如果有）。假设：使用我们的铅是消极的VN/14-1，我们已经建立了这类Rambas在许多体外和体内人类和鼠乳腺癌模型中的功效的原理证明。如本修订的应用中所述，要测试的主要假设是，第二代非典型Rambas的开发（识别），VN/14-1的新类似物具有增强的代谢稳定性，吸毒和疗效的增强，可能会作为乳腺癌的新疗法（抑制肿瘤生长和转移）。目的：检验这一假设，并最大程度地提高实现我们的最终目标的可能性，同时使用资源最有效地实现了四个特定的目标：1）综合铅VN/14-1的对映异构体，以修改VN/14-1的对照组，以修改更有效的/代谢/代谢稳定/富有代谢的药物类似类的类似物； 2）广泛表征和评估新的类似物作为rambas和人类乳腺癌细胞的抗增殖剂； 3）确定人类乳腺癌细胞系中铅化合物和最佳类似物的作用机理； 4）测试铅化合物和最佳类似物，以抑制乳腺癌生长的能力，抑制体内乳腺癌转移并鉴定疗效标志。意义：我们的最终目标是发现和开发能够抑制肿瘤细胞和转移生长的乳腺癌的新口服药物。重要的是，非典型Rambas抑制内分泌敏感和内分泌耐药性（对内分泌疗法的难治性）乳腺癌，并且还拮抗子宫增生，这些特征与选择性雌激素受体调节剂（SERMS）（例如Tamoxifen和atamoxifen和aromatase抑制剂）不同。拟议的研究如果成功进行的研究将鉴定至少一个或两个高度优化的，口腔效率的非典型rambas，适合于乳腺癌治疗的晚期临床前发育。这些研究还将导致鉴定在临床试验中有用的生物标志物。